It has been observed early life is an important time for the development of tolerogenic responses. This time is also correlated to the establishment of the intestinal microbiota, which is also necessary for the development of tolerance. However, it is unclear why tolerance is established best during early life and how the microbiota confers an effect on the immune system. Here I show gut resident bacteria spontaneously translocate from the intestinal lumen to the mesenteric lymph nodes during early life. This process occurs as part of normal development, yet the details of this phenomenon remain undefined. Adult mice can be manipulated through the use of antibiotics to induce bacterial translocation, which requires goblet-cell-associated antigen passages (GAPs) and CX3CR1+ antigen presenting cells (APCs). In this grant I will define when bacterial translocation occurs during early life, what species translocate, from where the species originate, and to which organs species translocate using 16S deep sequencing of murine organs throughout early life. I will also investigate if bacterial translocation during early life requires GAPs and CX3CR1+ APCs, similar to adult mice, and if manipulation of GAPs or CX3CR1+ APCs disrupt bacterial translocation using transgenic mice and pharmacological manipulation of GAPs. Finally, I will evaluate the role bacterial translocation has in the development of regulatory T cells and systemic tolerance using flow cytometry and a delayed type hypersensitivity model of systemic inflammation. Completion of this project will define the novel process of physiologic bacterial translocation during early lfe, how it is regulated and what effects it has on the immune system, providing insight into how the intestinal microbiota contributes to the development of tolerance and the effect disruption of bacterial translocation during early life has on lifelong immune responses.

Public Health Relevance

While it is thought live bacteria within the body indicates infection, the presence of live bacteria originating from the intestines can be found within lymph nodes during early life as a part of normal development. I am investigating what species are found within the organs at this time, and how they contribute to the education of the immune system. This work has novel implications into how intestinal bacteria confer signals for the establishment of tolerance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Saslowsky, David E
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Mayo Clinic, Rochester
United States
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Kulkarni, Devesha H; McDonald, Keely G; Knoop, Kathryn A et al. (2018) Goblet cell associated antigen passages are inhibited during Salmonella typhimurium infection to prevent pathogen dissemination and limit responses to dietary antigens. Mucosal Immunol 11:1103-1113
Knoop, Kathryn A; Gustafsson, Jenny K; McDonald, Keely G et al. (2017) Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Sci Immunol 2:
McDonald, Keely G; Wheeler, Leroy W; McDole, Jeremiah R et al. (2017) CCR6 promotes steady-state mononuclear phagocyte association with the intestinal epithelium, imprinting and immune surveillance. Immunology 152:613-627
Chai, Jiani N; Peng, Yangqing; Rengarajan, Sunaina et al. (2017) Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci Immunol 2:
Knoop, Kathryn A; Gustafsson, Jenny K; McDonald, Keely G et al. (2017) Antibiotics promote the sampling of luminal antigens and bacteria via colonic goblet cell associated antigen passages. Gut Microbes 8:400-411